Guanidinylamino heterocycle compounds useful as alpha-2 adrenoceptor agonists

ABSTRACT

This invention involves compounds having the structure (I) as described in the claims, and enantiomers,optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters thereof, as well as pharmaceutical compositions comprising such noved compounds. The invention also relates to the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.

This application claim benefit to provisional application Ser. No.60/031,756 Nov. 25, 1996.

TECHNICAL FIELD

This invention relates to certain substituted guanidinylaminoheterocycle compounds. The compounds have been found to be alpha-2adrenoceptor agonists and are useful for treatment of disordersmodulated by alpha-2 adrenoceptors.

BACKGROUND OF THE INVENTION

Therapeutic indications of alpha-2 adrenoceptor agonists have beendiscussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M.Stadel, & J. P. Hieble, “Pharmacologic and Therapeutic Applications ofAlpha-2 Adrenoceptor Subtypes”, Annual Review of Pharmacology &Toxicology, Vol. 32 (1993) pp. 243-279.

Information regarding alpha adrenergic receptors, agonists andantagonists, in general, and regarding compounds related in structure tothose of this invention are disclosed in the following references:Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, “12.1α-Adrenergic Receptors”, Comprehensive Medicinal Chemistry, Vol. 3,Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press(1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten,“α-Adrenoceptor Agonists and Antagonists”, Drugs of the Future, Vol. 9,No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F.H. L. Awouters & C. J. E. Niemegeers, “Further Validation of in vivo andin vitro Pharmacological Procedures for Assessing the α₁ andα₂-electivity of Test Compounds: (2) α-Adrenoceptor Agonists”, EuropeanJournal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B.M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P.A. van Zwieten, “Quantitative Relationships between α-AdrenergicActivity and Binding Affinity of α-Adrenoceptor Agonists andAntagonists”, Journal of Medicinal Chemistry, Vol. 27 (1984) pp.495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P.A. van Zwieten, “Selectivity of Some Alpha Adrenoceptor Agonists forPeripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat”,The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No.3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M.Myers, C. F. C. Smith & M. R. Stillings, “Effect of 1,4-DioxanylSubstitution on the Adrenergic Activity of Some Standardα-Adrenoreceptor Agents”, European Journal of Medicinal Chemistry, Vol.24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England,P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F.Tulloch, “Heteroaromatic Analogues of the α₂-Adrenoreceptor PartialAgonist Clonidine”, Journal of Medicinal Chemistry, Vol. 32 (1989), pp.1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, “Effects ofα₂-Adrenoceptor Agonists and of Related Compounds on Aggregation of, andon Adenylate Cyclase Activity in, Human Platelets”, British Journal ofPharmacology, Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat.No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, manycompounds related in structure to those of this invention do not providethe activity and specificity desirable when treating disorders modulatedby alpha-2 adrenoceptors.

For example, many compounds found to be effective nasal decongestantsare frequently found to have undesirable side effects, such as causinghypertension and insomnia at systemically effective doses. There is aneed for new drugs which provide relief from nasal congestion withoutcausing these undesirable side effects.

OBJECTS OF THE INVENTION

It is an object of the invention to provide compounds and compositionsuseful in treating disorders modulated by alpha-2 adrenoceptors.

It is an object of this invention to provide novel compounds havingsubstantial activity in preventing or treating nasal congestion, otitismedia, and sinusitis, without undesired side effects.

It is also an object of this invention to provide novel compounds fortreating cough, chronic obstructive pulmonary disease (COPD) and/orasthma.

It is also an object of this invention to provide novel compounds fortreating diseases and disorders associated with sympathetic nervoussystem activity, including benign prostatic hypertrophy, cardiovasculardisorders comprising myocardial ischemia, cardiac reperfusion injury,angina, cardiac arrhythmia, heart failure and hypertension.

It is also an object of this invention to provide novel compounds fortreating ocular disorders, such as ocular hypertension, glaucoma,hyperemia, conjunctivitis and uveitis.

It is also an object of this invention to provide novel compounds fortreating gastrointestinal disorders, such as diarrhea, irritable bowelsyndrome, hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).

It is also an object of this invention to provide novel compounds fortreating migraine.

It is also an object of this invention to provide novel compounds fortreating pain, substance abuse and/or withdrawal.

It is a still further object of this invention to provide such compoundswhich have good activity from peroral, parenteral, intranasal and/ortopical dosing.

SUMMARY OF THE INVENTION

This invention relates to compounds having the following structure:

a) R₁ is hydrogen; or alkyl or nil; where R₁ is nil, bond (a) is adouble bond;

b) D is CR₂ where R₂ is selected from hydrogen; unsubstituted C₁-C₃alkanyl; amino, hydroxy, mercapto; C₁-C₃ alkylthio or alkoxy; C₁-C₃alkylamino or C₁-C₃ dialkylamino and halo; or when B is CR₃, D may be N;

c) B is NR₉, CR₃═CR₈, CR₃═N, CR₃, S, O, SO or SO₂; wherein R₉ isselected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl;cycloalkanyl, cycloalkenyl and wherein R₃ and R₈ are each independentlyselected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl;cycloalkanyl, cycloalkenyl; unsubstituted C₁-C₃ alkylthio or alkoxy;hydroxy; thio; nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃dialkylamino and halo;

d) R₄, R₅ and R₆ are each independently selected from hydrogen;unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; cycloalkanyl,cycloalkenyl; unsubstituted C₁-C₃ alkylthio or alkoxy; hydroxy; thio;nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃ dialkylamino; halo; andNH—NH—C(═NR₁₀)NHR₁₁ (guanidinylamino); wherein R₁₀ and R₁₁ areindependently selected from hydrogen; methyl; and ethyl; and wherein oneand only one of R₄, R₅ and R₆ is guanidinylamino;

e) R₇ is selected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl oralkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C₁-C₃ alkylthio oralkoxy; hydroxy; thio; nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃dialkylamino and halo;

and enantiomers, optical isomers, stereoisomers, diastereomers,tautomers, addition salts, biohydrolyzable amides and esters, andpharmaceutical compositions containing such novel compounds, and the useof such compounds for preventing or treating disorders modulated byalpha-2 adrenoceptors.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “alkanyl” means a saturated hydrocarbon substituent,straight or branched chain, unsubstituted or substituted.

As used herein, “alkenyl” means a hydrocarbon substituent with onedouble bond, straight or branched chain, unsubstituted or substituted.

As used herein, “alkylthio” means a substituent having the structureQ—S—, where Q is alkanyl or alkenyl.

As used herein, “alkoxy” means a substituent having the structure Q—O—,where Q is alkanyl or alkenyl.

As used herein, “alkylamino” means a substituent having the structureQ—NH—, where Q is alkanyl or alkenyl.

As used herein, “dialkylamino” means a substituent having the structureQ₁—N(Q₂)—, where each Q is independently alkanyl or alkenyl.

“Guanidinylamino” is defined as a radical of structure;

For purposes of exemplifying this radical, wherever it appears in achart, it is shown as “GNDNLAM” for brevity.

“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodo.

A “pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987, incorporated by reference herein. Preferred cationic saltsinclude the alkali metal salts (such as sodium and potassium), alkalineearth metal salts (such as magnesium and calcium) and organic salts.Preferred anionic salts include halides, sulfonates, carboxylates,phosphates, and the like. Clearly contemplated in such salts areaddition salts that may provide an optical center, where once there wasnone. For example, a chiral tartrate salt may be prepared from thecompounds of the invention, and this definition includes such chiralsalts.

The compounds of the invention are sufficiently basic to formacid-addition salts. The compounds are useful both in the free base formand the form of acid-addition salts, and both forms are within thepurview of the invention. The acid-addition salts are in some cases amore convenient form for use. In practice, the use of the salt forminherently amounts to the use of the base form of the active. Acids usedto prepare acid-addition salts include preferably those which produce,when combined with the free base, medicinally acceptable salts. Thesesalts have anions that are relatively innocuous to the animal organism,such as a mammal, in medicinal doses of the salts so that the beneficialproperty inherent in the free base are not vitiated by any side effectsascribable to the acid's anions.

Examples of appropriate acid-addition salts include, but at not limitedto hydrochloride, hydrobromide, hydroiodiode, sulfate, hydrogensulfate,acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate,stearate, succinate, mallate, malonate, adipate, glutarate, lactate,propionate, butyrate, tartrate, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate,cyclohexanesulfamate, and the like. However, other appropriatemedicinally acceptable salts within the scope of the invention are thosederived from other mineral acids and organic acids. The acid-additionsalts of the basic compounds are prepared by several methods. Forexample the free base can be dissolved in an aqueous alcohol solutioncontaining the appropriate acid and the salt is isolated by evaporationof the solution. Altematively, they may be prepared by reacting the freebase with an acid in an organic solvent so that the salt separatesdirectly. Where separation of the salt is difficult, it can beprecipitated with a second organic solvent, or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention. All acid-addition salts are useful as sources of the freebase form, even if the particular salt per se is desired only as anintermediate product. For example, when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by ion exchangeprocedures, these salts are clearly contemplated to be a part of thisinvention.

“Biohydrolyzable amide” refers to an amide of the compound of theinvention that is readily converted in vivo by a mammal subject to yieldan active compound of the invention.

A “biohydrolyzable ester” refers to an ester of the compound of theinvention that is readily converted by a mammal subject to yield anactive compound of the invention.

“Optical isomer”, “stereoisomer”, “enantiomer,” “diastereomer,” asreferred to herein have the standard art recognized meanings (Cf.,Hawleys Condensed Chemical Dictionarv, 11th Ed.). Of course, an additionsalt may provide an optical center, where once there was none. Forexample, a chiral tartrate salt may be prepared from the compounds ofthe invention, and this definition includes such chiral salts. It willbe apparent to the skilled artisan that disclosure of the racemicmixture alone discloses any enantiomers therein. Thus by one disclosure,more than one compound is taught.

As used herein “animal” includes “mammals” which includes “humans”.

The skilled artisan will appreciate that tautomeric forms will exist incertain compounds of the invention. For example, when R₂ is hydroxy andbond (a) is a double bond, it is understood to include the keto form ofthat molecule, where R₂ is oxo, and bond (a) is a single bond, thoughnot specifically described. Thus, in this description the disclosure ofone tautomeric form discloses each and all of the tautomers. Similarly,when tautomer A of the molecule is shown, it is understood to includetautomers B and C of that molecule although not specifically depicted.

The illustration by scheme of example of specific protected forms andother derivatives of the Formula (I) compounds is not intended to belimiting. The application of other useful protecting groups, salt forms,etc. is within the ability of the skilled artisan.

As defined above and as used herein, substituent groups may themselvesbe substituted. Such substitution may be with one or more substituents.Such substituents include those listed in C. Hansch and A. Leo,Substituent Constants for Correlation Analysis in Chemistry and Biology(1979), incorporated by reference herein. Preferred substituents include(for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino,aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyacetyl(e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.),imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinationsthereof.

For the purposes of nomenclature, as shown in the following example, thelocation of the guanidinylamino radical is denoted:

It is recognized that where B is CR₃=CR₈, CR₃=N and the like, thisnumbering is not in strict compliance with IUPAC nomenclature. It isused for illustration of synthetic methods only; examples of compoundshave names which more closely resemble IUPAC nomenclature.

Compounds

This invention includes compounds having the following structure:

as described in the Summary of the Invention.

In the above structure, when the guanidinylamino is at the 6-position,preferably R₇ is selected from hydrogen; unsubstituted alkanyl oralkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthioor alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano;and halo. R₄ is preferably hydrogen, cyano, halo or methyl. R₇ is alsopreferably alkanyl, more preferably methyl or ethyl, most preferablymethyl. R₇ which is alkylthio or alkoxy is preferably saturated, alsopreferably C₁ or C₂, most preferably methyfthio or methoxy. R₇ which ishalo is preferably chloro or bromo.

In the above structure, when the guanidinylamino is at the 5-position,preferably R₄ is selected from hydrogen; unsubstituted alkanyl oralkenyl having 1 to about 3 carbon atoms; unsubstituted alkylthio oralkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano; andhalo. R₇ is preferably alkanyl or halo. R₄ and R₇ are most preferablymethyl.

In the above structure, when the guanidinylamino is at the 4-position,preferably R₇ is selected from hydrogen; unsubstituted alkanyl oralkenyl having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano;and halo. R₇ which is alkanyl, is preferably methyl or ethyl, morepreferably methyl. R₇ which is halo is preferably chloro or bromo. R₆ ispreferably hydrogen; alkanyl; cyano; and halo. R₆ which is alkanyl ispreferably methyl or ethyl, most preferably methyl. R₅ is preferablyhydrogen; alkanyl; and halo. R₅ which is alkanyl is preferably methyl orethyl, most preferably methyl.

Methods of making the compounds of the invention

The compounds of this invention are synthesized using the followingprocedures. For purposes of this description, 6-guanidinylaminocompounds are shown, but the skilled artisan will appreciate that the 4-and 5-guanidinylamino compounds are prepared similarly. The R₁-R₇radicals are omitted for clarity, unless they are prepared in thatspecific scheme. The skilled artisan will appreciate that the radicalsomitted are added using techniques known in the art. The skilled artisanwill also appreciate that the methods described may be used withblocking groups and the like, as appropriate.

Guanidinylamino groups are conveniently prepared from nitro and aminocompounds via the following example synthetic sequences:

Preferably these compounds are made from nitro or amino compounds.(Nitro and amino compounds are made by known processes.) The compoundsmay be manipulated to resuft in the suitably substitutedhydrazinoheterocycle. This hydrazinoheterocycle is then reacted usingknown methods to produce the guanidinylamino derivative. For example,the hydrazino compound may be reacted with cyanamide (H₂NCN) in acid toprovide the guanidinylamino compound. Aftematively, the hydrazinocompound may be reacted with a guanidine precursor, such as an alkylpseudothiourea or protected alkyl pseudothiourea in the presence of amercuric salt or the like.

The above starting nitro and amino compounds are obtained via one ormore synthetic steps comprising alkylations, halogenations (usuallybrominations), and halogen displacement reactions. Again, for clarity,the R₁-R₇ radicals are omitted. In the schemes below, a6-guanidinylamino precursor is described. The skilled artisan willreadily appreciate that 4-guanidinylamino and 5-guanidinylaminocompounds are prepared by analogous methods. These reaction types aresummarized below;

ALKYLATION REACTION:

FLUORINATION:

HALOGENATION, PREFERABLY BROMINATION:

Preferably, chlorination is accomplished using Cl₂, and iodination, bylCl using the same reactions.

HALOGEN DISPLACEMENT REACTIONS:

It will be apparent to the skilled artisan that the reactionsillustrated above are known reactions. Furthermore, it is within thepurview of the skilled artisan to vary these reactions to preparecompounds within the scope of the claims.

In the above schemes, where an R is alkoxy or alkylthio, thecorresponding hydroxy or thiol compounds are derived from the finalcompounds by using a standard dealkylating procedure (Bhatt, et al.,“Cleavage of Ethers”, Synthesis, 1983, pp. 249-281).

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available as astarting material.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterifications and saponifications and the like. Thesemanipulations are discussed in standard texts such as March, AdvancedOrganic Chemistry (Wiley), Carey and Sundberg, Advanced OrganicChemistry (2 vol.) and Trost and Fleming Comprehensive Organic Synthesis(6 vol.). The skilled artisan will readily appreciate that certainreactions are best carried out when other functionality is masked orprotected in the molecule, thus avoiding any undesirable side reactionsand/or increasing the yield ofthe reaction. Often the skilled artisanutilizes protecting groups to accomplish such increased yields or toavoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations are found, for example, in T.Greene, Protecting Groups in Organic Synthesis.

Compound Examples

The following non-limiting examples provide details for the synthesis ofguanidinylamino heterocycles:

EXAMPLE 1

[(8-Methylguinolin-7-yl)amino]quanidine

A. 8-Methyl-7-nitroquinoline. To a suspension of 2 g of2-methyl-3-nitroaniline and 1.02 g of arsenic(V) oxide hydrate are added2.88 mL of glycerin followed by 1.09 mL of concentrated sulfuric acid.The resulting black slurry is stirred at about 150° C. for 4 hours. Theblack oil is cooled to room temperature, diluted with water and pouredinto a mixture of 25% aqueous ammonium hydroxide in ethyl acetate. Theorganic layer is washed with water followed by brine. The aqueous layersare extracted with ethyl acetate; the combined organic layers are driedover magnesium sulfate, filtered and rotary evaporated. The residue ispurified by flash column chromatography on silica gel, eluting with 50%ethyl acetate/hexanes followed by recrystallization fromhexanesimethylene chloride to provide 1.45 g of8-methyl-7-nitroquinoline as a pale brown solid.

B. 7-Amino-8-methylguinoline. To a solution of 1.45 g of8-methyl-7-nitroquinoline in 20 mL of ethanol are added 1.45 g ofammonium formate and a catalytic amount of 10% palladium-on-carbon. Theresulting suspension is stirred at room temperature for 3 hours. Thereaction mixture is filtered on Celite, with a methanol wash of thesolids, and the filtrate is rotary evaporated. The residue is purifiedby flash column chromatography on silica gel, eluting with 50% ethylacetate/hexanes followed by recrystallization from hexanes/methylenechloride to provide 1.10 g of 7-amino-8-methylquinoline as a pale yellowsolid.

C. [(8-Methylquinolin-7-yl)amino]guanidine, dihydrochloric acid salt. Toa cold (−5° C.) suspension of 400 mg of 7-amino-8-methylquinoline in 1mL of concentrated hydrochloric acid is added a cold (−5° C.) solutionof 192 mg of sodium nitrite in 1 mL of water. The resulting suspensionis stirred at −5° C. for 1 hour, and a solution of 1.05 g of stannouschloride in 5 mL of concentrated hydrochloric acid is added at once. Ayellow precipitate forms immediately and the reaction mixture is stirredat 0° C. for 1 hour. The reaction mixture is filtered to provide 341 mgof hydrazine hydrochloride as a yellow solid.

To a mixture of the above hydrazine hydrochloride and 273 mg ofcyanamide are added 0.5 mL of concentrated hydrochloric acid and 0.2 mLof water. The resulting brown oil is stirred at 90° C. for 30 minutes.The reaction mixture is cooled to 0° C., and 1 mL of water and 1 mL ofconcentrated hydrochloric acid are added. A precipitate forms and themixture is kept in the freezer for 34 hours. The reaction mixture isthen rotary evaporated and the residue is dissolved in hot methanol andethyl acetate is added dropwise to the point of cloudiness. The solidthat forms is filtered to provide 320 mg of[(8-methylquinolin-7-yl)amino]guanidine, dihydrochloric acid salt as ayellow solid.

Example 2

[(4-Methylbenzimidazol-5-yl)amino]guanidine

A.2.3-Diamino-6-nitrotoluene. To a solution of 30 g of3-methyl-2,4-dinitroaniline in 750 mL of boiling ethanol is addeddropwise over 90 minutes a solution of 109.6 g of sodium sulfidenonahydrate in 750 mL of water. At the end of the addition, the mixtureis heated to reflux for 30 minutes, then poured into ice (2000 g) andallowed to stand until all the ice has melted. The mixture is thenextracted with methylene chloride and the organic layer is dried overmagnesium sulfate and rotary evaporated. The residue is purified byflash column chromatography on silica gel, eluting with methylenechloride to provide 2,3-diamino6-nitrotoluene as an orange solid.

B. 4-Methyl-5-nitrobenzimidazole. A mixture of 11.8 g of2,3-diamino-6-nitrotoluene, 390 mL of 88% formic acid and 38 mL of 12Nhydrochloric acid is heated to reflux for 1 hour. The resulting mixtureis cooled to room temperature and rotary evaporated. The residue isdiluted with 200 mL of water, then basified with ammonium hydroxide(28-30%). The suspension is extracted with ethyl acetate (3×200 mL). Thecombined extracts are dried over magnesium sulfate and rotary evaporatedto provide 4-methyl-5-nitrobenzimidazole as an orange solid.

C. 1-tert-Butoxycarbonyl-4-methyl-5-nitrobenzimidazole. A suspension of11.2 g of 4-methyl-5-nitrobenzimidazole, 21.58 g ofdi-tert-butyl-dicarbonate, 11.7 mL of triethylamine and 100 mg of4-dimethylaminopyridine in methanol (800 mL) and ethyl acetate (400 mL)is stirred at room temperature overnight. The mixture is rotaryevaporated and the residue purified by flash column chromatography onsilica gel, eluting with 10% ethyl acetate in hexanes. Theproduct-containing fractions are combined and rotary evaporated toafford a white solid contaminated with a yellow oil. The solid isdissolved in methylene chloride and enough hexanes is added to causeprecipitation. The solid is filtered and washed with 50% methylenechloride/hexanes. The filtrate is rotary evaporated and the processrepeated until no more clean white solid is obtained by precipitation.The combined solid fractions are dried in vacuo to afford1-tert-butoxycarbonyl4-methyl-5-nitrobenzimidazole as a white solid.

D. 5-Amino-1-tert-butoxycarbonyl-4-methylbenzimidazole. To a solution of8 g of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole in 40 mL ofmethanol and 400 mL of ethyl acetate are added 500 mg of 10%palladium-on-carbon and 7.27 g of ammonium formate. The mixture isstirred at 50° C. for 2 hours, then filtered on Celite, with a methanolwash of the solids. The filtrate is rotary evaporated and the residuepartitioned between water and ethyl acetate. The organic layer is washedwith saturated ammonium chloride, dried over magnesium sulfate, filteredand rotary evaporated to afford 5-amino-1-tert-butoxycarbonyl4-methylbenzimidazole as an off-white solid.

E. [(4-Methylbenzimidazol-5-yl)amino]guanidine, dihydrochloric acidsalt. To a cold (−5° C.) suspension of 500 mg of1-(tert-butyloxycarbonyl)-5-amino-4-methylbenzimidazole in 1 mL ofconcentrated hydrochloric acid is added a cold (−5° C.) solution of 154mg of sodium nitrite in 0.5 mL of water. The resulting suspension isstirred at −5° C. for 15 minutes, and a solution of 843 mg of stannouschloride in 5 mL of concentrated hydrochloric acid is added at once. Awhite precipitate immediately forms and the reaction mixture is stirredat <0° C. for 1 hour. The reaction mixture is filtered, the residue isdissolved in methanol, and reprecipitated by adding excess ether toprovide the hydrazine hydrochloride as a white solid. To a mixture ofthe hydrazine hydrochloride and 340 mg of cyanamide are added 0.5 mL ofconcentrated hydrochloric acid and 0.5 mL of water. The resulting paleyellow paste is stirred at 80° C. for 1 hour. The reaction mixture iscooled to 0° C., and 1 mL of water and 2 mL of concentrated hydrochloricacid are added. A precipitate forms and the mixture is kept in thefreezer for 3-4 hours. The reaction mixture is rotary evaporated and theresidue is dissolved in hot methanol and ethyl acetate is added dropwiseto the point of cloudiness. The solid that forms is filtered to provide360 mg of [(4-methylbenzimidazol-5-yl)amino]guanidine, dihydrochloricacid salt as an off-white solid.

Using the methodology outlined and exemplified above, the followingcompounds are made. In these examples where R₁ is nil, (a) is a doublebond, and guanidinylamino is signified by GNDNLAM;

In the following table, R₁₀=R₁₁=hydrogen.

Example R₁ D B R₄ R₅ R₆ R₇  3 nil CH NH Cl H GNDNLAM Me  4 nil CH NH BrH GNDNLAM Me  5 nil CH NH I H GNDNLAM Me  6 nil CH NH F H GNDNLAM Me  7nil CH NH OMe H GNDNLAM Me  8 nil CH NH Me H GNDNLAM Me  9 nil CH NH CNH GNDNLAM Me  10 nil CH NH Cl H GNDNLAM Et  11 nil CH NH Br H GNDNLAM Et 12 nil CH NH I H GNDNLAM Et  13 nil CH NH F H GNDNLAM Et  14 nil CH NHMe H GNDNLAM Et  15 nil CH NH H H GNDNLAM Et  16 nil CH NH Cl H GNDNLAMBr  17 nil CH NH Br H GNDNLAM Br  18 nil CH NH I H GNDNLAM Br  19 nil CHNH F H GNDNLAM Br  20 nil CH NH OMe H GNDNLAM Br  21 nil CH NH Me HGNDNLAM Br  22 nil CH NH CN H GNDNLAM Br  23 nil CH NH H H GNDNLAM Br 24 nil CH NH Cl H GNDNLAM Cl  25 nil CH NH Br H GNDNLAM Cl  26 nil CHNH I H GNDNLAM Cl  27 nil CH NH F H GNDNLAM Cl  28 nil CH NH OMe HGNDNLAM Cl  29 nil CH NH Me H GNDNLAM Cl  30 nil CH NH CN H GNDNLAM Cl 31 nil CH NH H H GNDNLAM Cl  32 nil CH NH Cl H GNDNLAM OMe  33 nil CHNH Br H GNDNLAM OMe  34 nil CH NH I H GNDNLAM OMe  35 nil CH NH F HGNDNLAM OMe  36 nil CH NH OMe H GNDNLAM OMe  37 nil CH NH Me H GNDNLAMOMe  38 nil CH NH CN H GNDNLAM OMe  39 nil CH NH H H GNDNLAM OMe  40 nilCH NH Cl H GNDNLAM SMe  41 nil CH NH Br H GNDNLAM SMe  42 nil CH NH I HGNDNLAM SMe  43 nil CH NH F H GNDNLAM SMe  44 nil CH NH OMe H GNDNLAMSMe  45 nil CH NH Me H GNDNLAM SMe  46 nil CH NH CN H GNDNLAM SMe  47nil CH NH H H GNDNLAM SMe  48 nil CH NH H Me GNDNLAM Me  49 nil CH NH HMe GNDNLAM Et  50 nil CH NH H Me GNDNLAM Br  51 nil CH NH H Me GNDNLAMCl  52 nil CH NH H Me GNDNLAM OMe  53 nil CH NH H Me GNDNLAM SMe  54 nilCH NH H OMe GNDNLAM Me  55 nil CH NH H OMe GNDNLAM Et  56 nil CH NH HOMe GNDNLAM Br  57 nil CH NH H OMe GNDNLAM Cl  58 nil CH NH H OMeGNDNLAM OMe  59 nil CH NH H OMe GNDNLAM SMe  60 nil CH NH H SMe GNDNLAMMe  61 nil CH NH H SMe GNDNLAM Et  62 nil CH NH H SMe GNDNLAM Br  63 nilCH NH H SMe GNDNLAM Cl  64 nil CH NH H SMe GNDNLAM OMe  65 nil CH NH HSMe GNDNLAM SMe  66 nil CH NH H Br GNDNLAM Me  67 nil CH NH H Br GNDNLAMEt  68 nil CH NH H Br GNDNLAM Br  69 nil CH NH H Br GNDNLAM Cl  70 nilCH NH H Br GNDNLAM OMe  71 nil CH NH H Br GNDNLAM SMe  72 nil CH NH H ClGNDNLAM Me  73 nil CH NH H Cl GNDNLAM Cl  74 nil CH NH Me Me GNDNLAM Me 75 nil CH NH Me Cl GNDNLAM Me  76 nil CH NH Me Br GNDNLAM Me  77 nil CHNH Me I GNDNLAM Me  78 nil CHMe NH H H GNDNLAM Me  79 nil CHMe NH H HGNDNLAM Et  80 nil CHMe NH H H GNDNLAM OMe  81 nil CH NMe H H GNDNLAM Me 82 nil CH S H H GNDNLAM Me  83 nil CH S Me H GNDNLAM Me  84 nil CH SOMe H GNDNLAM Me  85 nil CH S Br H GNDNLAM Me  86 nil CH S Cl H GNDNLAMMe  87 nil CH S F H GNDNLAM Me  88 ni CH S I H GNDNLAM Me  89 nil CH SCN H GNDNLAM Me  90 nil CH S H H GNDNLAM Et  91 nil CH S Me H GNDNLAM Et 92 nil CH S OMe H GNDNLAM Et  93 nil CH S Br H GNDNLAM Et  94 nil CH SCl H GNDNLAM Et  95 nil CH S F H GNDNLAM Et  96 nil CH S I H GNDNLAM Et 97 nil CH S CN H GNDNLAM Et  98 nil CH S H H GNDNLAM OMe  99 nil CH SMe H GNDNLAM OMe 100 nil CH S OMe H GNDNLAM OMe 101 nil CH S Br HGNDNLAM OMe 102 nil CH S Cl H GNDNLAM OMe 103 nil CH S F H GNDNLAM OMe104 nil CH S I H GNDNLAM OMe 105 nil CH S CN H GNDNLAM OMe 106 nil CH SH H GNDNLAM SMe 107 nil CH S Me H GNDNLAM SMe 108 nil CH S OMe H GNDNLAMSMe 109 nil CH S Br H GNDNLAM SMe 110 nil CH S Cl H GNDNLAM SMe 111 nilCH S F H GNDNLAM SMe 112 nil CH S I H GNDNLAM SMe 113 nil CH S CN HGNDNLAM SMe 114 nil CH S H H GNDNLAM Br 115 nil CH S Me H GNDNLAM Br 116nil CH S OMe H GNDNLAM Br 117 nil CH S Br H GNDNLAM Br 118 nil CH S Cl HGNDNLAM Br 119 nil CH S F H GNDNLAM Br 120 nil CH S I H GNDNLAM Br 121nil CH S CN H GNDNLAM Br 122 nil CH S H Me GNDNLAM H 123 nil CH S H OMeGNDNLAM H 124 nil CH S H Br GNDNLAM H 125 nil CH S H Me GNDNLAM Me 126nil CH S H OMe GNDNLAM Me 127 nil CH S H Br GNDNLAM Me 128 nil CH S H MeGNDNLAM Et 129 nil CH S H OMe GNDNLAM Et 130 nil CH S H Br GNDNLAM Et131 nil CH S H Me GNDNLAM Br 132 nil CH S H OMe GNDNLAM Br 133 nil CH SH Br GNDNLAM Br 134 nil CH S H Me GNDNLAM OMe 135 nil CH S H OMe GNONLAMOMe 136 nil CH S H Br GNDNLAM OMe 137 nil CH S H Me GNDNLAM SMe 138 nilCH S H OMe GNDNLAM SMe 139 nil CH S H Br GNDNLAM SMe 140 H CH═ ═CH H HGNDNLAM Me 141 H CH═ ═C(Br) H H GNDNLAM Me 142 H CH₂ CH₂ H H GNDNLAM Me143 H N═ ═CH H H GNDNLAM Me 144 H N═ ═CH H H GNDNLAM Et 145 H N═ ═CH H HGNDNLAM Br 146 nil CH O H H GNDNLAM Me 147 nil CH CH═CH Cl H GNDNLAM Me148 nil CH CH═CH Br H GNDNLAM Me 149 nil CH CH═CH I H GNDNLAM Me 150 nilCH CH═CH F H GNDNLAM Me 151 nil CH CH═CH OMe H GNDNLAM Me 152 nil CHCH═CH Me H GNDNLAM Me 153 nil CH CH═CH CN H GNDNLAM Me 154 nil CH CH═CHCl H GNDNLAM Et 155 nil CH CH═CH Br H GNDNLAM Et 156 nil CH CH═CH I HGNDNLAM Et 157 nil CH CH═CH F H GNDNLAM Et 158 nil CH CH═CH OMe HGNDNLAM Et 159 nil CH CH═CH Me H GNDNLAM Et 160 nil CH CH═CH CN HGNDNLAM Et 161 nil CH CH═CH H H GNDNLAM Et 162 nil CH CH═CH Cl H GNDNLAMBr 163 nil CH CH═CH Br H GNDNLAM Br 164 nil CH CH═CH I H GNDNLAM Br 165nil CH CH═CH F H GNDNLAM Br 166 nil CH CH═CH OMe H GNONLAM Br 167 nil CHCH═CH Me H GNDNLAM Br 168 nil CH CH═CH CN H GNDNLAM Br 169 nil CH CH═CHH H GNDNLAM Br 170 nil CH CH═CH Cl H GNDNLAM Cl 171 nil CH CH═CH Br HGNDNLAM Cl 172 nil CH CH═CH I H GNDNLAM Cl 173 nil CH CH═CH F H GNDNLAMCl 174 nil CH CH═CH OMe H GNDNLAM Cl 175 nil CH CH═CH Me H GNDNLAM Cl176 nil CH CH═CH CN H GNDNLAM Cl 177 nil CH CH═CH H H GNDNLAM Cl 178 nilCH CH═CH Cl H GNDNLAM OMe 179 nil CH CH═CH Br H GNDNLAM OMe 180 nil CHCH═CH I H GNDNLAM OMe 181 nil CH CH═CH F H GNDNLAM OMe 182 nil CH CH═CHOMe H GNDNLAM OMe 183 nil CH CH═CH Me H GNDNLAM OMe 184 nil CH CH═CH CNH GNDNLAM OMe 185 nil CH CH═CH H H GNDNLAM OMe 186 nil CH CH═CH Cl HGNDNLAM SMe 187 nil CH CH═CH Br H GNDNLAM SMe 188 nil CH CH═CH I HGNDNLAM SMe 189 nil CH CH═CH F H GNDNLAM SMe 190 nil CH CH═CH OMe HGNDNLAM SMe 191 nil CH CH═CH Me H GNDNLAM SMe 192 nil CH CH═CH CN HGNDNLAM SMe 193 nil CH CH═CH H H GNDNLAM SMe 194 nil CH CH═CH H MeGNDNLAM Me 195 nil CH CH═CH H Me GNDNLAM Et 196 nil CH CH═CH H MeGNDNLAM Br 197 nil CH CH═CH H Me GNDNLAM Cl 198 nil CH CH═CH H MeGNDNLAM OMe 199 nil CH CH═CH H Me GNDNLAM SMe 200 nil CH CH═CH H OMeGNDNLAM Me 201 nil CH CH═CH H OMe GNDNLAM Et 202 nil CH CH═CH H OMeGNDNLAM Br 203 nil CH CH═CH H OMe GNDNLAM Cl 204 nil CH CH═CH H OMeGNDNLAM OMe 205 nil CH CH═CH H OMe GNDNLAM SMe 206 nil CH CH═CH H SMeGNDNLAM Me 207 nil CH CH═CH H SMe GNDNLAM Et 208 nil CH CH═CH H SMeGNDNLAM Br 209 nil CH CH═CH H SMe GNDNLAM Cl 210 nil CH CH═CH H SMeGNDNLAM OMe 211 nil CH CH═CH H SMe GNDNLAM SMe 212 nil CH CH═CH H BrGNDNLAM Me 213 nil CH CH═CH H Br GNDNLAM Et 214 nil CH CH═CH H BrGNDNLAM Br 215 nil CH CH═CH H Br GNDNLAM Cl 216 nil CH CH═CH H BrGNDNLAM OMe 217 nil CH CH═CH H Br GNDNLAM SMe 218 nil CH CH═CH H ClGNDNLAM Me 219 nil CH CH═CH H Cl GNDNLAM Cl 220 nil CH CH═CH Me MeGNDNLAM Me 221 nil CH CH═CH Me Cl GNDNLAM Me 222 nil CH CH═CH Me BrGNDNLAM Me 223 nil CH CH═CH Me I GNDNLAM Me 224 nil CH CH═CH Me GNDNLAMH Cl 225 nil CH CH═CH Me GNDNLAM H Br 226 nil CH CH═CH Me GNDNLAM H I227 nil CH CH═CH Me GNDNLAM H Me 228 nil CH CH═CH Et GNDNLAM H Cl 229nil CH CH═CH Et GNDNLAM H Br 230 nil CH CH═CH Et GNDNLAM H I 231 nil CHCH═CH Et GNDNLAM H Me 232 nil CH CH═CH Br GNDNLAM H Cl 233 nil CH CH═CHBr GNDNLAM H Br 234 nil CH CH═CH Br GNDNLAM H I 235 nil CH CH═CH BrGNDNLAM H Me 236 nil CH CH═CH Cl GNDNLAM H Cl 237 nil CH CH═CH ClGNDNLAM H Br 238 nil CH CH═CH Cl GNDNLAM H I 239 nil CH CH═CH Cl GNDNLAMH Me 240 nil CH CH═CH OMe GNDNLAM H Cl 241 nil CH CH═CH OMe GNDNLAM H Br242 nil CH CH═CH OMe GNDNLAM H I 243 nil CH CH═CH OMe GNDNLAM H Me 244nil CH CH═CH SMe GNDNLAM H Cl 245 nil CH CH═CH SMe GNDNLAM H Br 246 nilCH CH═CH SMe GNDNLAM H I 247 nil CH CH═CH SMe GNDNLAM H Me 248 nil CHCH═CH Me GNDNLAM Me H 249 nil CH CH═CH Me GNDNLAM Br H 250 nil CH CH═CHMe GNDNLAM Cl H 251 nil CH CH═CH Me GNDNLAM OMe H 252 nil CH CH═CH MeGNDNLAM SMe H 253 nil CH CH═CH Et GNDNLAM Me H 254 nil CH CH═CH EtGNDNLAM Br H 255 nil CH CH═CH Et GNDNLAM Cl H 256 nil CH CH═CH EtGNDNLAM OMe H 257 nil CH CH═CH Et GNDNLAM SMe H 258 nil CH CH═CH BrGNDNLAM Me H 259 nil CH CH═CH Br GNDNLAM Br H 260 nil CH CH═CH BrGNDNLAM Cl H 261 nil CH CH═CH Br GNDNLAM OMe H 262 nil CH CH═CH BrGNDNLAM SMe H 263 nil CH CH═CH Cl GNDNLAM Me H 264 nil CH CH═CH ClGNDNLAM Br H 265 nil CH CH═CH Cl GNDNLAM Cl H 266 nil CH CH═CH ClGNDNLAM OMe H 267 nil CH CH═CH Cl GNDNLAM SMe H 268 nil CH CH═CH OMeGNDNLAM Me H 269 nil CH CH═CH OMe GNDNLAM Br H 270 nil CH CH═CH OMeGNDNLAM Cl H 271 nil CH CH═CH OMe GNDNLAM OMe H 272 nil CH CH═CH OMeGNDNLAM SMe H 273 nil CH CH═CH SMe GNDNLAM Me H 274 nil CH CH═CH SMeGNDNLAM Br H 275 nil CH CH═CH SMe GNDNLAM OMe H 276 nil CH CH═CH SMeGNDNLAM SMe H 277 nil CH CH═CH Me GNDNLAM Me Me 278 nil CH C(Me)═CH MeGNDNLAM H Me 279 nil CH C(Br)═CH Me GNDNLAM H Me 280 nil CH C(Cl)═CH MeGNDNLAM H Me 281 nil CH C(F)═CH Me GNDNLAM H Me 282 nil CH CH═C(Me) MeGNDNLAM H Me 283 nil CH CH═C(CN) Me GNDNLAM H Me 284 nil CH CH═C(Br) MeGNDNLAM H Me 285 nil CH CH═C(Cl) Me GNDNLAM H Me 286 nil CH CH═C(F) MeGNDNLAM H Me 287 nil CH S Me GNDNLAM H Me 288 nil CH S Me GNDNLAM H Cl289 nil CH S Me GNDNLAM H Br 290 nil CH S Me GNDNLAM H I 291 nil CH S MeGNDNLAM H OMe 292 nil CH S Cl GNDNLAM H Me 293 nil CH S Cl GNDNLAM H Cl294 nil CH S Cl GNDNLAM H Br 295 nil CH S Cl GNDNLAM H I 296 nil CH S ClGNDNLAM H OMe 297 nil CH S Br GNDNLAM H Me 298 nil CH S Br GNDNLAM H Cl299 nil CH S Br GNDNLAM H Br 300 nil CH S Br GNDNLAM H I 301 nil CH S BrGNDNLAM H OMe 302 nil CH S I GNDNLAM H Me 303 nil CH S I GNDNLAM H Cl304 nil CH S I GNDNLAM H Br 305 nil CH S I GNDNLAM H I 306 nil CH S IGNDNLAM H OMe 307 nil CH S Et GNDNLAM H Me 308 nil CH S Et GNDNLAM H Cl309 nil CH S Et GNDNLAM H Br 310 nil CH S Et GNDNLAM H I 311 nil CH S EtGNDNLAM H OMe 312 nil CH S Me GNDNLAM Me H 313 nil CH S Me GNDNLAM Cl H314 nil CH S Me GNDNLAM Br H 315 nil CH S Me GNDNLAM I H 316 nil CH S ClGNDNLAM Cl H 317 nil CH S Me GNDNLAM Me Me 318 nil CH S Me GNDNLAM Cl Me319 nil CH S Me GNDNLAM Br Me 320 nil CH S Me GNDNLAM I Me 321 nil CH SEt GNDNLAM H Me 322 nil CH S Et GNDNLAM H Me 323 H CH═ ═CH GNDNLAM H H H324 H CH═ ═CH GNDNLAM H H Me 325 H CH═ ═CH GNDNLAM H H Et 326 H CH═ ═CHGNDNLAM H H CN 327 H CH═ ═CH GNDNLAM H H Br 328 H CH═ ═CH GNDNLAM H H Cl329 H CH═ ═CH GNDNLAM H H I 330 H CH═ ═CH GNDNLAM H Me H 331 H CH═ ═CHGNDNLAM H CN H 332 H CH═ ═CH GNDNLAM H Br H 333 H CH═ ═CH GNDNLAM H Cl H334 H CH═ ═CH GNDNLAM H I H 335 H CH═ ═C(Me) GNDNLAM H H H 336 H CH══C(Et) GNDNLAM H H H 337 H CH═ ═C(Br) GNDNLAM H H H 338 H CH═ ═C(Cl)GNDNLAM H H H 339 H CH═ ═C(CN) GNDNLAM H H H 340 H CH═ ═CH GNONLAM Me HH 341 H CH═ ═CH GNDNLAM Br H H 342 H CH₂ CH₂ GNDNLAM H H H

In the following table, R₁₀=Me and R₁₁=H.

343 nil CH NH H H GNDNLAM Me 344 nil CH NH H H GNDNLAM Br 345 nil CHCH═CH H H GNDNLAM Me 346 nil CH CH═CH Me GNDNLAM H Me 347 nil CH S H HGNDNLAM Me 348 nil CH S H H GNDNLAM Br

In the following table, R₁₀=Et and R₁₁=H.

349 nil CH N H H GNDNLAM Me 350 nil CH CH═CH H H GNDNLAM Me 351 nil CHCH═CH Me GNDNLAM H Me 352 nil CH S H H GNDNLAM Me 353 nil CH S H HGNDNLAM Br

Compositions

Another aspect of this invention is compositions which comprise a safeand effective amount of a subject compound, or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable carrier.

As used herein, “safe and effective amount” means an amount of thesubject compound sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. A safe and effective amount of thesubject compound will vary with the age and physical condition of thepatient being treated, the severity of the condition, the duration ofthe treatment, the nature of concurrent therapy, the particularpharmaceutically-acceptable carrier utilized, and like factors withinthe knowledge and expertise of the attending physician.

Preparing a dosage form is within the purview of the skilled artisan.Examples are provided for the skilled artisan, but are non-limiting, andit is contemplated that the skilled artisan can prepare variations ofthe compositions claimed.

Compositions of this invention preferably comprise from about 0.0001% toabout 99% by weight of the subject compound, more preferably from about0.01% to about 90% of the compound of the invention. Depending upon theroute of administration and attendant bioavailability, solubility ordissolution characteristics of the dosage form, the dosage form haspreferably from about 10% to about 50%, also preferably from about 5% toabout 10%, also preferably from about 1% to about 5%, and alsopreferably from about 0.01% to about 1% of the subject compound. Thefrequency of dosing of the subject compound is dependent upon thepharmacokinetic properties of each specific agent (for example,biological half-life) and can be determined by the skilled artisan.

In addition to the subject compound, the compositions of this inventioncontain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Preferably when liquid doseforms are used, the compounds of the invention are soluble in thecomponents of the composition. Pharmaceutically-acceptable carriersmust, of course, be of sufficiently high purity and sufficiently lowtoxicity to render them suitable for administration to the mammal beingtreated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions. The choice of a pharmaceutically-acceptable carrier to beused in conjunction with the subject compound is basically determined bythe way the compound is to be administered. If the subject compound isto be injected, the preferred pharmaceutically-acceptable carrier issterile, physiological saline, with a blood-compatible suspending agent,the pH of which has been adjusted to about 7.4.

If the preferred mode of administering the subject compound isperorally, the preferred unit dosage form is therefore tablets,capsules, lozenges, chewable tablets, and the like. Such unit dosageforms comprise a safe and effective amount of the subject compound,which is preferably from about 0.01 mg to about 350 mg, more preferablyfrom about 0.1 mg to about 35 mg, based on a 70 kg person. Thepharmaceutically-acceptable carrier suitable for the preparation of unitdosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of thisinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.001% toabout 5% of the subject compound, more preferably from about 0.01% toabout 0.5%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, Avicel® RC-591, tragacanth and sodium alginate;typical wetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual and buccal dosage forms. Such compositionstypically comprise one or more of soluble filler substances such assucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions can also be used to deliver the compound to the site whereactivity is desired: intranasal doses for nasal decongestion, inhalantsfor asthma, and eye drops, gels and creams for ocular disorders.

Preferred compositions of this invention include solutions or emulsions,preferably aqueous solutions or emulsions comprising a safe andeffective amount of a subject compound intended for topical intranasaladministration. Such compositions preferably comprise from about 0.001%to about 25% of a subject compound, more preferably from about 0.01% toabout 10%. Similar compositions are preferred for systemic delivery ofsubject compounds by the intranasal route. Compositions intended todeliver the compound systemically by intranasal dosing preferablycomprise similar amounts of a subject compound as are determined to besafe and effective by peroral or parenteral administration. Suchcompositions used for intranasal dosing also typically include safe andeffective amounts of preservatives, such as benzalkonium chloride andthimerosal and the like; chelating agents, such as edetate sodium andothers; buffers such as phosphate, citrate and acetate; tonicity agentssuch as sodium chloride, potassium chloride, glycerin, mannitol andothers; antioxidants such as ascorbic acid, acetylcystne, sodiummetabisulfate and others; aromatic agents; viscosity adjustors, such aspolymers, including cellulose and derivatives thereof, and polyvinylalcohol and acids and bases to adjust the pH of these aqueouscompositions as needed. The compositions may also comprise localanesthetics or other actives. These compositions can be used as sprays,mists, drops, and the like.

Other preferred compositions of this invention include aqueoussolutions, suspensions, and dry powders comprising a safe and effectiveamount of a subject compound intended for atomization and inhalationadministration. Such compositions preferably comprise from about 0.1% toabout 50% of a subject compound, more preferably from about 1% to about20%; of course, the amount can be altered to fit the circumstance of thepatient contemplated and the package. Such compositions are typicallycontained in a container with attached atomizing means. Suchcompositions also typically include propellants such aschlorofluorocarbons 12/11 and 12/114, and more environmentally friendlyfluorocarbons, or other nontoxic volatiles; solvents such as water,glycerol and ethanol, these include cosolvents as needed to solvate orsuspend the active; stabilizers such as ascorbic acid, sodiummetabisulfite; preservatives such as cetylpyridinium chloride andbenzalkonium chloride; tonicity adjustors such as sodium chloride;buffers; and flavoring agents such as sodium saccharin. Suchcompositions are useful for treating respiratory disorders, such asasthma and the like.

Other preferred compositions of this invention include aqueous solutionscomprising a safe and effective amount of a subject compound intendedfor topical intraocular administration. Such compositions preferablycomprise from about 0.0001% to about 5% of a subject compound, morepreferably from about 0.01% to about 0.5%. Such compositions alsotypically include one or more of preservatives, such as benzalkoniumchloride, thimerosal, phenylmercuric acetate; vehicles, such aspoloxamers, modified celluloses, povidone and purified water; tonicityadjustors, such as sodium chloride, mannitol and glycerin; buffers suchas acetate, citrate, phosphate and borate; antioxidants such as sodiummetabisulfite, butylated hydroxy toluene and acetyl cysteine; acids andbases may be used to adjust the pH of these formulations as needed.

Other preferred compositions of this invention useful for peroraladministration include solids, such as tablets and capsules, andliquids, such as solutions, suspensions and emulsions (preferably insoft gelatin capsules), comprising a safe and effective amount of asubject compound. Such compositions preferably comprise from about 0.01mg to about 350 mg per dose, more preferably from about 0.1 mg to about35 mg per dose. Such compositions can be coated by conventional methods,typically with pH or time-dependent coatings, such that the subjectcompound is released in the gastrointestinal tract at various times toextend the desired action. Such dosage forms typically include, but arenot limited to, one or more of cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose, Eudragit® coatings, waxes and shellac.

Any of the compositions of this invention may optionally include otherdrug actives. Non-limiting examples of drug actives which may beincorporated in these compositions, include:

Antihistamines, including:

Hydroxyzine, preferably at a dosage range of from about 25 to about 400mg; Doxylamine, preferably at a dosage range of from about 3 to about 75mg; Pyrilamine, preferably at a dosage range of from about 6.25 to about200 mg; Chlorpheniramine, preferably at a dosage range of from about 1to about 24 mg; Phenindamine, preferably at a dosage range of from about6.25 to about 150 mg; Dexchlorpheniramine, preferably at a dosage rangeof from about 0.5 to about 12 mg; Dexbrompheniramine, preferably at adosage range of from about 0.5 to about 12 mg; Clemastine, preferably ata dosage range of from about 1 to about 9 mg; Diphenhydramine,preferably at a dosage range of from about 6.25 to about 300 mg;Azelastine, preferably at a dosage range of from about 140 to about1,680 μg (when dosed intranasally); 1 to about 8 mg (when dosed orally);Acrivastine, preferably at a dosage range of from about 1 to about 24mg; Levocarbastine (which can be dosed as an intranasal or ocularmedicament), preferably at a dosage range of from about 100 to about 800mg; Mequitazine, preferably at a dosage range of from about 5 to about20 mg; Astemizole, preferably at a dosage range of from about 5 to about20 mg; Ebastine, preferably at a dosage range of from about 5 to about20 mg; Loratadine, preferably at a dosage range of from about 5 to about40 mg; Cetirizine, preferably at a dosage range of from about 5 to about20 mg; Terfenadine, preferably at a dosage range of from about 30 toabout 480 mg; Terfenadine metabolites; Promethazine, preferably at adosage range of from about 6.25 to about 50 mg; Dimenhydrinate,preferably at a dosage range of from about 12.5 to about 400 mg;Meclizine, preferably at a dosage range of from about 6.25 to about 50mg; Tripelennamine, preferably at a dosage range of from about 6.25 toabout 300 mg; Carbinoxamine, preferably at a dosage range of from about0.5 to about 16 mg; Cyproheptadine, preferably at a dosage range of fromabout 2 to about 20 mg; Azatadine, preferably at a dosage range of fromabout 0.25 to about 2 mg; Brompheniramine, preferably at a dosage rangeof from about 1 to about 24 mg; Triprolidine, preferably at a dosagerange of from about 0.25 to about 10 mg; Cyclizine, preferably at adosage range of from about 12.5 to about 200 mg; Thonzylamine,preferably at a dosage range of from about 12.5 to about 600 mg;Pheniramine, preferably at a dosage range of from about 3 to about 75mg; Cyclizine, preferably at a dosage range of from about 12.5 to about200 mg and others;

Antitussives, including:

Codeine, preferably at a dosage range of from about 2.5 to about 120 mg;Hydrocodone, preferably at a dosage range of from about 2.5 to about 40mg; Dextromethorphan, preferably at a dosage range of from about 2.5 toabout 120 mg; Noscapine, preferably at a dosage range of from about 3 toabout 180 mg; Benzonatate, preferably at a dosage range of from about100 to about 600 mg; Diphenhydramine, preferably at a dosage range offrom about 12.5 to about 150 mg; Chlophedianol, preferably at a dosagerange of from about 12.5 to about 100 mg; Clobutinol, preferably at adosage range of from about 20 to about 240 mg; Fominoben, preferably ata dosage range of from about 80 to about 480 mg; Glaucine; Pholcodine,preferably at a dosage range of from about 1 to about 40 mg; Zipeprol,preferably at a dosage range of from about 75 to about 300 mg;Hydromorphone, preferably at a dosage range of from about 0.5 to about 8mg; Carbetapentane, preferably at a dosage range of from about 15 toabout 240 mg; Caramiphen, preferably at a dosage range of from about 10to about 100 mg; Levopropoxyphene, preferably at a dosage range of fromabout 25 to about 200 mg and others;

Antiinflammatories, preferably Non-Steroidal Anti-inflammatories,(NSAIDS) including:

Ibuprofen, preferably at a dosage range of from about 50 to about 3,200mg; Naproxen, preferably at a dosage range of from about 62.5 to about1,500 mg; Sodium naproxen, preferably at a dosage range of from about110 to about 1,650 mg; Ketoprofen, preferably at a dosage range of fromabout 25 to about 300 mg; Indoprofen, preferably at a dosage range offrom about 25 to about 200 mg; Indomethacin, preferably at a dosagerange of from about 25 to about 200 mg; Sulindac, preferably at a dosagerange of from about 75 to about 400 mg; Diflunisal, preferably at adosage range of from about 125 to about 1,500 mg; Ketorolac, preferablyat a dosage range of from about 10 to about 120 mg; Piroxicam,preferably at a dosage range of from about 10 to about 40 mg; Aspirin,preferably at a dosage range of from about 80 to about 4,000 mg;Meclofenamate, preferably at a dosage range of from about 25 to about400 mg; Benzydamine, preferably at a dosage range of from about 25 toabout 200 mg; Carprofen, preferably at a dosage range of from about 75to about 300 mg; Diclofenac, preferably at a dosage range of from about25 to about 200 mg; Etodolac, preferably at a dosage range of from about200 to about 1,200 mg; Fenbufen, preferably at a dosage range of fromabout 300 to about 900 mg; Fenoprofen, preferably at a dosage range offrom about 200 to about 3,200 mg; Flurbiprofen, preferably at a dosagerange of from about 50 to about 300 mg; Mefenamic acid, preferably at adosage range of from about 250 to about 1,500 mg; Nabumetone, preferablyat a dosage range of from about 250 to about 2,000 mg; Phenylbutazone,preferably at a dosage range of from about 100 to about 400 mg;Pirprofen, preferably at a dosage range of from about 100 to about 800mg; Tolmetin, preferably at a dosage range of from about 200 to about1,800 mg and others;

Analgesics, including:

Acetaminophen, preferably at a dosage range of from about 80 to about4,000 mg; and others:

Expectorants/Mucolytics, including:

Guaifenesin, preferably at a dosage range of from about 50 to about2,400 mg; N-Acetylcysteine, preferably at a dosage range of from about100 to about 600 mg; Ambroxol, preferably at a dosage range of fromabout 15 to about 120 mg; Bromhexine, preferably at a dosage range offrom about 4 to about 64 mg; Terpin hydrate, preferably at a dosagerange of from about 100 to about 1,200 mg; Potassium iodide, preferablyat a dosage range of from about 50 to about 250 mg and others;

Anticholinergics (e.g., Atropinics), preferably intranasally or orallyadministered anticholinergics, including:

Ipratroprium (preferably intranasally), preferably at a dosage range offrom about 42 to about 252 μg; Atropine sulfate (preferably oral),preferably at a dosage range of from about 10 to about 1,000 μg;Belladonna (preferably as an extract), preferably at a dosage range offrom about 15 to about 45 mg equivalents; Scopolamine, preferably at adosage range of from about 400 to about 3,200 μg; Scopolaminemethobromide, preferably at a dosage range of from about 2.5 to about 20mg; Homatropine methobromide, preferably at a dosage range of from about2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably at adosage range of from about 125 to about 1,000 μg; Isopropramide(preferably oral), preferably at a dosage range of from about 5 to about20 mg; Orphenadrine (preferably oral), preferably at a dosage range offrom about 50 to about 400 mg; Benzalkonium chloride (preferablyintranasally) preferably a 0.005 to about 0.1% solution and others;

Mast Cell Stabilizers, Dreferably intranasally, or orally administeredmast cell stabilizers, including:

Cromalyn, preferably at a dosage range of from about 10 to about 60 mg;Nedocromil, preferably at a dosage range of from about 10 to about 60mg; Oxatamide, preferably at a dosage range of from about 15 to about120 mg; Ketotifen, preferably at a dosage range of from about I to about4 mg; Lodoxamide, preferably at a dosage range of from about 100 toabout 3,000 μg and others;

Leukotriene Antagonists, including Zileuton and others;

Methylxanthines, including:

Caffeine, preferably at a dosage range of from about 65 to about 600 mg;Theophylline, preferably at a dosage range of from about 25 to about1,200 mg; Enprofylline; Pentoxifylline, preferably at a dosage range offrom about 400 to about 3,600 mg; Aminophylline, preferably at a dosagerange of from about 50 to about 800 mg; Dyphylline, preferably at adosage range of from about 200 to about 1,600 mg and others;

Antioxidants or radical inhibitors, including:

Ascorbic acid, preferably at a dosage range of from about 50 to about10,000 mg; Tocopherol, preferably at a dosage range of from about 50 toabout 2,000 mg; Ethanol, preferably at a dosage range of from about 500to about 10,000 mg and others;

Steroids, preferably intranasally administered steroids, including:

Beclomethasone, preferably at a dosage range of from about 84 to about336 μg; Fluticasone, preferably at a dosage range of from about 50 toabout 400 μg; Budesonide, preferably at a dosage range of from about 64to about 256 μg; Mometasone, preferably at a dosage range of from about50 to about 300 mg; Triamcinolone, preferably at a dosage range of fromabout 110 to about 440 μg; Dexamethasone, preferably at a dosage rangeof from about 168 to about 1,008 g; Flunisolide, preferably at a dosagerange of from about 50 to about 300 μg; Prednisone (preferably oral),preferably at a dosage range of from about 5 to about 60 mg;Hydrocortisone (preferably oral), preferably at a dosage range of fromabout 20 to about 300 mg and others;

Bronchodilators, preferably for inhalation, including:

Albuterol, preferably at a dosage range of from about 90 to about 1,080μg; 2 to about 16 mg (if dosed orally); Epinephrine, preferably at adosage range of from about 220 to about 1,320 μg; Ephedrine, preferablyat a dosage range of from about 15 to about 240 mg (if dosed orally);250 to about 1,000 μg (if dosed intranasally); Metaproterenol,preferably at a dosage range of from about 65 to about 780 μg or 10 toabout 80 mg if dosed orally; Terbutaline, preferably at a dosage rangeof from about 200 to about 2,400 μg; 2.5 to about 20 mg (if dosedorally); Isoetharine, preferably at a dosage range of from about 340 toabout 1,360 μg; Pirbuterol, preferably at a dosage range of from about200 to about 2,400 μg; Bitofterol, preferably at a dosage range of fromabout 370 to about 2,220 μg; Fenoterol, preferably at a dosage range offrom about 100 to about 1,200 μg; 2.5 to about 20 mg (if dosed orally);Rimeterol, preferably at a dosage range of from about 200 to about 1,600μg; Ipratroprium, preferably at a dosage range of from about 18 to about216 μg (inhalation) and others; and

Antivirals, including:

Amantadine, preferably at a dosage range of from about 50 to about 200mg; Rimantadine, preferably at a dosage range of from about 50 to about200 mg; Enviroxime; Nonoxinols, preferably at a dosage range of fromabout 2 to about 20 mg (preferably an intranasal form); Acyclovir,preferably at a dosage range of from about 200 to about 2,000 mg (oral);1 to about 10 mg (preferably an intranasal form); Alpha-interferon,preferably at a dosage range of from about 3 to about 36 MIU;Beta-interferon, preferably at a dosage range of from about 3 to about36 MIU and others;

Ocular Drug actives: acetylcholinesterase inhibitors, e.g.,echothiophate from about 0.03% to about 0.25% in topical solution andothers; and

Gastrointestinal actives: antidiarrheals, e.g., loperamide from about0.1 mg to about 1.0 mg per dose, and bismuth subsalicylate from about 25mg to about 300 mg per dose and others.

Of course, clearly contemplated and included in the description aboveare the acid or base addition salts, esters, metabolites, stereoisomersand enantiomers of these preferred combination actives, as well as theiranalogues of these actives that are safe and effective. It is alsorecognized that an active may be useful for more than one of the aboveuses, and these uses are clearly contemplated as well. This overlap isrecognized in the art and adjusting dosages and the like to fit theindication is well within the purview of the skilled medicalpractitioner.

Methods of use

Without being bound by theory, it is contemplated that the primarymechanism by which alpha-2 agonists provide efficacy is by interveningin the biological cascade responsible for disorder(s) and/ormanifestation(s) thereof. It may be that there is no deficit in alpha-2adrenoceptor activity: such activity may be normal. However,administration of an alpha-2 agonist may be a useful way of rectifying adisorder, condition or manifestation thereof.

Thus as used herein, the terms “disease,” “disorder” and “condition” areused interchangeably to refer to maladies related to or modulated byalpha-2 adrenoceptor activity.

As used herein, a disorder described by the terms “modulated by alpha-2adrenoceptors,” or “modulated by alpha-2 adrenoceptor activity” refersto a disorder, condition or disease where alpha-2 adrenoceptor activityis an effective means of alleviating the disorder or one or more of thebiological manifestations of the disease or disorder; or interferes withone or more points in the biological cascade either leading to thedisorder or responsible for the underlying disorder; or alleviates oneor more symptoms of the disorder. Thus, disorders subject to“modulation” include those for which:

The lack of alpha-2 activity is a “cause” of the disorder or one or moreof the biological manifestations, whether the activity was alteredgenetically, by infection, by irritation, by internal stimulus or bysome other cause;

The disease or disorder or the observable manifestation ormanifestations of the disease or disorder are alleviated by alpha-2activity. The lack of alpha-2 activity need not be causally related tothe disease or disorder or the observable manifestations thereof;

Alpha-2 activity interferes with part of the biochemical or cellularcascade that results in or relates to the disease or disorder. In thisrespect, the alpha-2 activity alters the cascade, and thus controls thedisease, condition or disorder.

The compounds of this invention are particularly useful for thetreatment of nasal congestion associated with allergies, colds, andother nasal disorders, as well as the sequelae of congestion of themucous membranes (for example, sinusitis and otitis media). At effectivedoses, it has been found that undesired side effects can be avoided.

While not limited to a particular mechanism of action, the subjectcompounds are believed to provide advantages in the treatment of nasaldecongestion over related compounds through their ability to interactwith alpha-2 adrenoceptors. The subject compounds have been found to bealpha-2 adrenoceptor agonists which cause constriction of peripheralvascular beds in the nasal turbinates.

Alpha-2 adrenoceptors are distributed both inside and outside of thecentral nervous system. Thus, though not essential for activity orefficacy, certain disorders preferably are treated with compounds thatact on alpha-2 adrenoceptors in only one of these regions. Compounds ofthis invention vary in their ability to penetrate into the centralnervous system and, thus, to produce effects mediated through centralalpha-2 adrenoceptors. Thus, for example, a compound which displays ahigher degree of central nervous system activity is preferred forcentral nervous system indications over other compounds as describedbelow. However, even for compounds that exhibit primarily peripheralactivity, central nervous system actions can be evoked by an increase inthe dose of the compound. Further specificity of action of thesecompounds can be achieved by delivering the agent to the region whereactivity is desired (for example, topical administration to the eye,nasal mucosa or respiratory tract).

Compounds preferred for, but not limited to, the treatment of certaincardiovascular disorders, pain, substance abuse and/or withdrawal, ulcerand hyperacidity include those compounds that are centrally acting. Bycentrally acting what is meant is that they have some action on thealpha-2 adrenoceptors in the central nervous system in addition to theiraction at peripheral alpha-2 adrenoceptors.

Compounds preferred for, but not limited to, the treatment ofrespiratory disorders, ocular disorders, migraine, certaincardiovascular disorders, and certain other gastrointestinal disordersare peripherally acting. By peripherally acting, what is meant is thatthese compounds act primarily on alpha-2 adrenoceptors in the periphery,rather than those in the central nervous system. Methods are availablein the art to determine which compounds are primarily peripherallyacting and which are primarily centrally acting.

Thus, compounds of the subject invention are also useful for thetreatment of ocular disorders such as ocular hypertension, glaucoma,hyperemia, conjunctivitis, and uveitis. The compounds are administeredeither perorally, or topically as drops, sprays, mists, gels or creamsdirectly to the surface of the mammalian eye.

The compounds of this invention are also useful for controllinggastrointestinal disorders, such as diarrhea, irritable bowel syndrome,hyperchlorhydria and peptic ulcer.

The compounds of this invention are also useful for diseases anddisorders associated with sympathetic nervous system activity, includinghypertension, myocardial ischemia, cardiac reperfusion injury, angina,cardiac arrhythmia, heart failure and benign prostatic hypertrophy. Dueto their sympatholytic effect, compounds are also useful as an adjunctto anesthesia during surgical procedures.

The compounds of this invention are also useful for relieving painassociated with various disorders. The compounds are administeredperorally, parenterally, and/or by direct injection into thecerebrospinal fluid.

The compounds of this invention are also useful for the prophylactic oracute treatment of migraine. The compounds are administered perorally,parenterally or intranasally.

The compounds of this invention are also useful for treatment ofsubstance abuse, in particular abuse of alcohol and opiates, andalleviating the abstinence syndromes evoked by withdrawal of thesesubstances.

The compounds of this invention are also useful for other diseases anddisorders where vasoconstriction, particularly of veins, would provide abenefit, including septic or cardiogenic shock, elevated intracranialpressure, hemmorhoids, venous insufficiency, varicose veins, andmenopausal flushing.

The compounds of this invention are also useful for neurologic diseasesand disorders, including spasticity, epilepsy, attention deficithyperactive disorder, Tourette's syndrome, and cognitive disorders.

The pharmacological activity and selectivity of these compounds can bedetermined using published test procedures. The alpha-2 selectivity ofthe compounds is determined by measuring receptor binding affinities andin vitro functional potencies in a variety of tissues known to possessalpha-2 and/or alpha-I receptors. (See, e.g., The Alpha-2 AdrenergicReceptors, L. E. Limbird, ed., Humana Press, Clifton, N.J.) Thefollowing in vivo assays are typically conducted in rodents or otherspecies. Central nervous system activity is determined by measuringlocomotor activity as an index of sedation. (See, e.g., Spyraki, C. & H.Fibiger, “Clonidine-induced Sedation in Rats: Evidence for Mediation byPostsynaptic Alpha-2 Adrenoreceptors”, Journal of Neural Transmission,Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is measuredusing rhinomanometry as an estimate of nasal airway resistance. (See,e.g., Salem, S. & E. Clemente, “A New Experimental Method for EvaluatingDrugs in the Nasal Cavity”, Archives of Otolaryngology, Vol. 96 (1972),pp. 524-529). Antiglaucoma activity is determined by measuringintraocular pressure. (See, e.g., Potter, D., “Adrenergic Pharmacologyof Aqueous Human Dynamics”, Pharmacological Reviews, Vol. 13 (1981), pp.133-153). Antidiarrheal activity is determined by measuring the abilityof the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g.,Thollander, M., P. Hellstrom & T. Svensson, “Suppression of CastorOil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists”, AlimentaryPharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy intreating irritable bowel syndrome is determined by measuring the abilityof compounds to reduce the stress-induced increase in fecal output.(See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro &H. Ormsbee III, “Cold-restraint stress increases rat fecal pellet outputand colonic transit”, American Journal of Physiology, Vol. 258 (1990),pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy isdetermined by measuring the reduction in gastric acid secretion producedby these compounds (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca &C. Roze, “Effect of α2-adrenoceptor agonists on gastric pepsin and acidsecretion in the rat”, British Journal of Pharmacology, Vol. 106 (1992),pp. 790-796). Antiasthma activity is determined by measuring the effectof the compound on bronchoconstriction associated with pulmonarychallenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser &J. Hand, “Effects of a Novel Leukotriene D₄ Antagonist with5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, onLeukotriene-D₄- and Antigen-induced Bronchoconstriction in Guinea Pig”,International Archives of Allergy and Applied Immunology, Vol. 86(1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B.Marchette, J. Stevenson & W. Abraham, “The Role of Slow-ReactingSubstance of Anaphylaxis in the Late Bronchial Response After AntigenChallenge in Allergic Sheep”, American Reviews of Respiratory Disease,Vol. 130 (1984), pp. 748-754). Activity in cough is determined bymeasuring the number and latency of the cough response to respiratorychallenges such as inhaled citric acid. (See, e.g., Callaway, J. & R.King, “Effects of Inhaled α2-Adrenoceptor and GABA_(B) Receptor Agonistson Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs”,European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195). Thesympatholytic activity of these compounds is determined by measuring thereduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo & K.Starke “Involvement of peripheral presynaptic inhibition in thereduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304”,European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or thereduction in renal sympathetic nerve activity (See, e.g., Feng, Q., S.Carlsson, P. Thoren & T. Hedner, “Effects of clonidine on renalsympathetic nerve activity, natriuresis and diuresis in chroniccongestive heart failure rats”, Journal of Pharmacology and ExperimentalTherapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis fortheir benefit in heart failure and benign prostatic hypertrophy. Thehypotensive effect of these compounds is measure directly as a reductionin mean blood pressure (See, e.g., Timmermans, P. & P. Van Zwieten,“Central and peripheral α-adrenergic effects of some imidazolidines”,European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236). Clinicalstudies have demonstrated the beneficial effect of alpha-2 agonists inthe prevention of myocardial ischemia during surgery (See, e.g., Talke,P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano,“Effects of Perioperative Dexmedetomidine Infusion in PatientsUndergoing Vascular Surgery”, Anesthesiology, Vol. 82 (1995), pp.620-633) and in the prevention of angina (See, e.g., Wright, R. A., P.Decroly, T. Kharkevitch & M. Oliver, “Exercise Tolerance in Angina isImproved by Mivazerol—an α2-Adrenoceptor Agonist”, Cardiovascular Drugsand Therapy, Vol. 7 (1993), pp. 929-934). The efficacy of thesecompounds in cardiac reperfusion injury is demonstrated by measuring thereduction of cardiac necrosis and neutrophil infiltration (See, e.g.,Weyrich, A., X. Ma, & A. Lefer, “The Role of L-Arginine in AmelioratingReperfusion Injury After Myocardial lschemia in the Cat”, Circulation,Vol. 86 (1992), pp. 279-288). The cardiac antiarrhythmic effect of thesecompounds is demonstrated by measuring the inhibition of ouabain inducedarrhythmias (See, e.g., Thomas, G. & P. Stephen, “Effects of TwoImidazolines (ST-91 and ST-93) on the Cardiac Arrhythmias and LethalityInduced by Ouabain in Guinea-Pig”, Asia-Pacific Journal of Pharmacology,Vol. 8 (1993), pp.109-113; and Samson, R., J. Cai, E. Shibata, J.Martins & H. Lee, “Electrophysiological effects of α2-adrenergicstimulation in canine cardiac Purkirje fibers”, American Journal ofPhysiology, Vol. 268 (1995), pp. H2024-H2035). The vasoconstrictoractivity of these compounds is demonstrated by measuring the contractileproperties on isolated arteries and veins in vitro (See, e.g., Flavahan,N., T. Rimele, J. Cooke & M. Vanhoutte, “Characterization ofPostjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenousor Nerve-Released Norepinephrine in the Canine Saphenous Vein”, Journalof Pharmacology and Experimental Therapeutics, Vol. 230 (1984), pp.699-705). The effectiveness of these compounds at reducing intracranialpressure is demonstrated by measurement of this property in a caninemodel of subarachnoid hemorrhage (See, e.g., McCormick, J., P.McCormick, J. Zabramski & R. Spetzler, “Intracranial pressure reductionby a central alpha-2 adrenoreceptor agonist after subarachnoidhemorrhage”, Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibitionof menopausal flushing is demonstrated by measuring the reduction offacial blood flow in the rat (See, e.g., Escott, K., D. Beattie, H.Connor & S. Brain, “The modulation of the increase in rat facial skinblood flow observed after trigeminal ganglion stimulation”, EuropeanJournal of Pharmacology, Vol. 284 (1995), pp. 69-76) as demonstrated foralpha-2 adrenergic agonists on cutaneous blood flow in the tail (See,e.g., Redfem, W., M. MacLean, R. Clague & J. McGrath, “The role ofalpha-2 adrenoceptors in the vasculature of the rat tail”, BritishJournal of Pharmacoloay, Vol. 114 (1995), pp. 1724-1730). Theantinociceptive and pain reducing properties of these compounds isdemonstrated by measuring the increase in pain threshold in the rodentwrithing and hot plate antinociceptive models (See, e.g., Millan, M., K.Bervoets, J. Rivet, R. Widdowson, A. Renouard, S, Le Marouille-Girardon& A. Gobert, “Multiple Alpha-2 Adrenergic Receptor Subtypes. II.Evidence for a Role of Rat Alpha-2A Adrenergic Receptors in the Controlof Nociception, Motor Behavior and Hippocampal Synthesis ofNoradrenaline”, Journal of Pharmacology and Experimental Therapeutics,Vol. 270 (1994), pp. 958-972). The antimigraine effect of thesecompounds is demonstrated by measuring the reduction of dural neurogenicinflammation to trigeminal ganglion stimulation in the rat (See, e.g.,Matsubara, T., M. Moskowitz & Z. Huang, “UK-14,304,R(−)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakagewithin dura mater by prejunctional mechanisms”, European Journal ofPharmacology, Vol. 224 (1992), pp. 145-150). The ability of thesecompounds to suppress opiate withdrawal is demonstrated by measuring thesuppression of enhanced sympathetic nerve activity (See, e.g., Franz,D., D. Hare & K. McCloskey, “Spinal sympathetic neurons: possible sitesof opiate-withdrawal suppression by clonidine”, Science, Vol. 215(1982), pp. 1643-1645). Antiepileptic activity of these compounds isdemonstrated by measuring the inhibition of the kindling response (See,e.g., Shouse, M., M. Bier, J. Langer, O. Alcalde, M. Richkind & R.Szymusiak, “The α2-agonist clonidine suppresses seizures, whereas thealpha-2 antagonist idazoxan promotes seizures—a microinfusion study inamygdala-kindled kittens”, Brain Research, Vol. 648 (1994), pp.352-356). The effectiveness of other alpha-2 agonists in the managementof neurologic disorders has been demonstrated, includingattention-deficit hyperactive disorder and Tourette's syndrome (See,e.g., Chappell P., M. Riddle, L. Scahill, K. Lynch, R. Schultz, A.Amsten, J. Leckman & D. Cohen, “Guanfacine treatment of comorbidattention-deficit hyperactivity disorder and Tourette's syndrome:preliminary clinical experience”, Journal of American Academy of Childand Adolescent Psychiatry, Vol. 34 (1995), pp. 1140-1146), cognitivedisorders (See, e.g., Coull, J., “Pharmacological manipulations of theα2-noradrenergic system. Effects on cognition”, Drugs and Aging, Vol. 5(1994), pp. 116-126), and spasticity (See, e.g., Eyssette, M., F.Rohmer, G. Serratrice, J. Warter & D. Boisson, “Multicenter,double-blind trial of a novel antispastic agent, tizanidine, inspasticity associated with multiple sclerosis”, Current Medical Research& Opinion, Vol. 10 (1988), pp. 699-708).

Another aspect of this invention involves methods for preventing ortreating nasal congestion by administering a safe and effective amountof a subject compound to a mammal experiencing or at risk ofexperiencing nasal congestion. Such nasal congestion may be associatedwith human diseases or disorders which include, but are not limited to,seasonal allergic rhinitis, acute upper respiratory viral infections,sinusitis, perennial rhinitis, and vasomotor rhinitis. In addition,other disorders can be generally associated with mucous membranecongestion (for example, otitis media and sinusitis.) Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of acompound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.Peroral administration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily. Such doses and frequencies arealso preferred for treating other respiratory conditions, such as,cough, chronic obstructive pulmonary disease (COPD) and asthma. Suchdoses and frequencies are also preferred for treating conditions thatare associated with mucous membrane congestion (for example, sinusitisand otitis media).

Another aspect of this invention involves methods for preventing ortreating glaucoma by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingglaucoma. If administered systemically, each administration of a dose ofthe subject compound preferably administers a dose within the range offrom about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferablyfrom about 0.001 mg/kg to about 0.5 mg/kg. If intraocular dosing is usedthen preferably one administers a typical volume (for example, 1 or 2drops) of a liquid composition, comprising from about 0.0001% to about5% of a subject compound, more preferably from about 0.01% to about 0.5%of the compound. Determination of the exact dosage and regimen is withinthe purview of the skilled artisan. Intraocular administration of suchdoses is preferred. The frequency of administration of a subjectcompound according to this invention is preferably from about once toabout six times daily, more preferably from about once to about 4 timesdaily.

Another aspect of this invention involves methods for preventing ortreating gastrointestinal disorders, such as diarrhea, irritable bowelsyndrome, and peptic ulcer by administering a safe and effective amountof a subject compound to a mammal experiencing or at risk ofexperiencing gastrointestinal disorders. Each administration of a doseof the subject compound preferably administers a dose within the rangeof from about 0.0001 mg/kg to about 5 mg/kg of a compound, morepreferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroraladministration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating migraine, by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingmigraine. Each administration of a dose of the subject compoundpreferably administers a dose within the range of from about 0.0001mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001mg/kg to about 0.5 mg/kg. Peroral, parenteral or intranasaladministration of such doses is preferred. The frequency of peroraladministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily. The frequency of parenteraldosing of subject compound according to this invention is preferablyfrom about once to about six times daily, more preferably from aboutonce to about 4 times daily or by infusion to the desired effect. Thefrequency of intranasal dosing of a subject compound according to thisinvention is preferably from about once to about six times daily, morepreferably from about once to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating disorders related to sympathetic nervous system activity, suchas hypertension, myocardial ischemia, cardiac reperfusion injury,angina, cardiac arrhythmia, and benign prostatic hypertrophy, byadministering a safe and effective amount of a subject compound to amammal experiencing or at risk of experiencing these diseases ordisorders. Each administration of a dose of the subject compoundpreferably administers a dose within the range of from about 0.0001mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001mg/kg to about 0.5 mg/kg. Peroral and parenteral administration of suchdoses are preferred. The frequency of peroral administration of asubject compound according to this invention is preferably from aboutonce to about six times daily, more preferably from about once to about4 times daily. The frequency of parenteral dosing of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about once to about 4 times daily orby infusion to the desired effect.

Another aspect of this invention involves methods for preventing ortreating pain, by administering a safe and effective amount of a subjectcompound to a mammal experiencing or at risk of experiencing pain. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of acompound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.Peroral or parenteral administration of such doses is preferred. Thefrequency of peroral administration of a subject compound according tothis invention is preferably from about once to about six times daily,more preferably from about once to about 4 times daily. The frequency ofparenteral dosing of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily or by infusion to the desiredeffect.

Another aspect of this invention involves methods for preventing ortreating substance abuse and the abstinence syndrome resulting fromwithdrawal of these substances, such as alcohol and opiates, byadministering a safe and effective amount of a subject compound to amammal experiencing or at risk of experiencing substance abuse orwithdrawal symptoms. Each administration of a dose of the subjectcompound preferably administers a dose within the range of from about0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about0.001 mg/kg to about 0.5 mg/kg. Peroral administration of such doses ispreferred. The frequency of administration of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about once to about 4 times daily.

Composition and Method Examples

The following non-limiting examples illustrate the compositions andmethods of use of this invention.

Example A

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 2 20.0 Microcrystalline cellulose (Avicel PH 102 ®) 80.0Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil ®) 1.0 Magnesiumstearate 3.0 Total = 200.0 mg

One tablet is swallowed by a patient with nasal congestion. Thecongestion is substantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example B

Chewable Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 1 15.0 Mannitol 255.6 Microcrystalline cellulose (Avicel PH101 ®) 100.8 Dextrinized sucrose (Di-Pac ®) 199.5 Imitation orangeflavor 4.2 Sodium saccharin 1.2 Stearic acid 15.0 Magnesium stearate 3.0FD&C Yellow #6 dye 3.0 Pyrogenic silica (Cab-O-Sil ®) 2.7 Total = 600.0mg

One tablet is chewed and swallowed by a patient with nasal congestion.The congestion is substantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example C

Sublingual Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 2 2.00 Mannitol 2.00 Microcrystalline cellulose (Avicel PH101 ®) 29.00 Mint flavorants 0.25 Sodium saccharin 0.08 Total = 33.33 mg

One tablet is placed under the tongue of a patient with nasal congestionand allowed to dissolve. The congestion is rapidly and substantiallydiminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example D

Intranasal Solution Composition Ingredient Composition (% w/v) SubjectCompound 1 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total = 100.00

One-tenth of a mL of the composition is sprayed from a pump actuatorinto each nostril of a patient with nasal congestion. The congestion issubstantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example E

Intranasal Gel Composition Ingredient Composition (% w/v) SubjectCompound 1 0.10 Benzalkonium chloride 0.02 Thimerosal 0.002Hydroxypropyl methylcellulose 1.00 (Metolose 65SH4000 ®) Aromatics 0.06Sodium chloride (0.65%) q.s. Total = 100.00

One-fifth of a mL of the composition is applied as drops from a dropperinto each nostril of a patient with nasal congestion. The congestion issubstantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example F

Inhalation Aerosol Composition Ingredient Composition (% w/v) SubjectCompound 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 SodiumSaccharin 0.2 Propellant (F12, F114) q.s. Total = 100.0

Two-puffs of the aerosol composition is inhaled from a metered-doseinhaler by a patient with asthma. The asthmatic condition is effectivelyrelieved.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example G

Topical Ophthalmic Composition Ingredient Composition (% w/v) SubjectCompound 1 0.10 Benzalkonium chloride 0.01 EDTA 0.05Hydroxyethylcellulose (Natrosol M ®) 0.50 Sodium metabisulfite 0.10Sodium chloride (0.9%) q.s. Total = 100.0

One-tenth of a mL of the composition is administered directly into eacheye of a patient with glaucoma. The intraocular pressure issubstantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example H

Oral Liquid Composition Ingredient Amount/15 mL Dose Subject Compound 215 mg Chlorpheniramine maleate 4 mg Propylene glycol 1.8 g Ethanol (95%)1.5 mL Methanol 12.5 mg Eucalyptus oil 7.55 mg Flavorants 0.05 mLSucrose 7.65 g Carboxymethylcellulose (CMC) 7.5 mg Microcrystallinecellulose and 187.5 mg Sodium CMC (Avicel RC 591 ®) Polysorbate 80 3.0mg Glycerin 300 mg Sorbitol 300 mg FD&C Red #40 dye 3 mg Sodiumsaccharin 22.5 mg Sodium phosphate monobasic 44 mg Sodium citratemonohydrate 28 mg Purified Water q.s. Total = 15 mL

One 15 mL dose of the liquid composition is swallowed by a patient withnasal congestion and runny nose due to allergic rhinitis. The congestionand runny nose are effectively reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example J

Oral Liquid Composition Ingredient Amount/15 mL Dose Subject Compound 230 mg Sucrose 8.16 g Glycerin 300 mg Sorbitol 300 mg Methylparaben 19.5mg Propylparaben 4.5 mg Menthol 22.5 mg Eucalyptus oil 7.5 mg Flavorants0.07 mL FD&C Red #40 dye 3.0 mg Sodium saccharin 30 mg Purified waterq.s. Total = 15 mL

One 15 mL dose of the alcohol-free liquid medication is swallowed by apatient with nasal congestion. The congestion is substantiallydiminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example K

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 1 4 Microcrystalline cellulose, NF 130 Starch 1500, NF 100Magnesium stearate, USP 2 Total = 236 mg

One tablet is swallowed by a patient with migraine. The pain and aura ofmigraine is substantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example L

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 2 12 Hydroxypropyl methylcellulose, USP 12 Magnesium stearate,USP 2 Lactose anhydrous, USP 200 Total = 226 mg

For the relief of pain. Adults 12 and over take one tablet every twelvehours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example M

Oral Caplet Composition Ingredient Amount per tablet (mg) Naproxensodium anhydrous, USP 220 Subject Compound 1 6 Hydroxypropylmethylcellulose, USP 6 Magnesium stearate, USP 2 Povidone K-30, USP 10Talc, USP 12 Microcrystalline cellulose, NF 44 Total = 300 mg

For relief of symptoms associated with the common cold, sinusitis, orflu including nasal congestion, headache, fever, body aches, and pains.Adults 12 and over take two caplets every twelve hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example N

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 2 6 Hydroxypropyl methylcellulose, USP 6 Silicon dioxide,colloidal, NF 30 Pregelatinized starch, NF 50 Magnesium stearate, USP 4Total = 96 mg

For treatment of benign prostatic hypertrophy. Take one tablet per day.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example O

Oral Tablet Composition Ingredient Amount per caplet (mg) SubjectCompound 1 6 Hydroxypropyl methylcellulose, USP 6 Magnesium stearate,USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF44 Total = 80 mg

For the use in the treatment of alcoholism or opiate addiction. Adults12 and over take two caplets every twelve hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example P

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 1 6 Hydroxypropyl methylcellulose, USP 12 Magnesium stearate,USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF44 Total = 86 mg

For the treatment of ulcer and hyperacidity. Take two tablets asappropriate.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example Q

Oral Tablet Composition Ingredient Amount per tablet (mg) ComponentAmount Subject Compound 2 10 mg/ml carrier Carrier: Sodium citratebuffer with (percent by weight of carrier): Lecithin 0.48%Carboxymethylcellulose 0.53 Povidone 0.50 Methyl paraben 0.11 Propylparaben 0.011

For the reduction of cardiac reperfusion injury.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example R

Oral Liquid Composition Ingredient Amount/fl oz Dose (mg) Acetaminophen,USP 1000 Doxylamine succinate, USP 12.5 Dextromethorphan hydrobromide,USP 30 Subject Compound 2 6 Dow XYS-40010.00 resin 3 High fructose cornsyrup 16000 Polyethylene glycol, NF 3000 Propylene glycol, USP 3000Alcohol, USP 2500 Sodium citrate dihydrate, USP 150 Citric acid,anhydrous, USP 50 Saccharin sodium, USP 20 Flavor 3.5 Purified water,USP 3500 Total = 29275 mg/fl oz

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example S

Oral Liquid Composition Ingredient Amount/fl oz Dose (mg) Naproxensodium anhydrous, USP 220 Doxylamine succinate, USP 12.5Dextromethorphan hydrobromide, USP 30 Subject Compound 1 6 DowXYS-40010.00 resin 3 High fructose corn syrup 16000 Polyethylene glycol,NF 3000 Propylene glycol, USP 3000 Alcohol, USP 2500 Sodium citratedihydrate, USP 150 Citric acid, anhydrous, USP 50 Saccharin sodium, USP20 Flavor 3.5 Purified water, USP 3800 Total = 28795 mg/fl oz

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Composition Example T

A composition for parenteral administration, according to thisinvention, is made comprising:

Component Amount Subject Compound I 10 mg/ml carrier Carrier: Sodiumcitrate buffer with (percent by weight of carrier): Lecithin 0.48%Carboxymethylcellulose 0.53 Povidone 0.50 Methyl paraben 0.11 Propylparaben 0.011

The above ingredients are mixed, forming a solution. Approximately 2.0ml of the solution is administered, intravenously, to a human subjectsuffering from septic or cardiogenic shock. The symptoms subside.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example U

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 2 10 Hydroxypropyl methylcellulose, USP 12 Magnesium stearate,USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystalline cellulose, NF44 Total = 90 mg

For the treatment of cardiac arrhythmia. Take as prescribed.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example V

Oral Tablet Composition Ingredient Amount per tablet (mg) SubjectCompound 1 4 Microcrystalline cellulose, NF 130 Starch 1500, NF 100Magnesium stearate, USP 2 Total = 236 mg

For the treatment of congestive heart failure. Take as prescribed.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Modification of the preceding embodiments is within the scope of theskilled artisan in formulation, given the guidance of the specificationin light of the state of the art.

Other examples of combination actives are contemplated. Examples ofmedicaments which can be combined with the primary active are includedin U.S. Pat. No. 4,552,899 to Sunshine, et al., hereby incorporated byreference. All other references referred to throughout thisspecification are hereby incorporated by reference.

While particular embodiments of this invention have been described, itwill be obvious to those skilled in the art that various changes andmodifications of this invention can be made without departing from thespirit and scope of the invention. It is intended to cover, in theappended claims, all such modifications that are within the scope ofthis invention.

What is claimed is:
 1. A compound of formula;

wherein; a) R₁ is hydrogen; or alkyl or nil; where R₁ is nil, bond (α)is a double bond; b) D is CR₂ where R₂ is selected from hydrogen;unsubstituted C₁-C₃ alkanyl; amino, hydroxy, mercapto; C₁-C₃ alkylthioor alkoxy; C₁-C₃ alkylamino; c) B is NR₉ wherein R₉ is selected fromhydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; cycloalkanyl,and cycloalkenyl; d) R₄, R₅ and R₆ are each independently selected fromhydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; cycloalkanyl,cycloalkenyl; unsubstituted C₁-C₃ alkylthio or alkoxy; hydroxy; thio;nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃ dialkylamino; halo; andNH—NH—C(—NR₁₀)NHR₁₁ (guanidinylamino); wherein R₁₀ and R₁₁ areindependently selected from hydrogen; methyl; and ethyl; and wherein oneand only one of R₄, R₅ and R₆ is guanidinylamino; e) R₇ is selected fromhydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; cycloalkanyl,cycloalkenyl, unsubstituted C₁-C₃ alkylthio or alkoxy; hydroxy; thio;nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃ dialkylamino and halo; oran enantiomer, optical isomer, stereoisomer, diastereomer, tautomer,addition salt, biohydrolyzable amide and ester thereof.
 2. A compoundaccording to claim 1 wherein R₆ is guanidinylamino and R₁₁ is hydrogen.3. A compound according to claim 2 wherein B is NR₉ and D is CR₂.
 4. Acompound according to claim 3 wherein R₂, R₉ and R₁₀ are eachindependently chosen from hydrogen and methyl; R₄ is selected fromhydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano; R₅ ishydrogen; and R₇ is selected from methyl, chloro, and bromo.
 5. Thecompound according to claim 2, wherein: R₄ is selected from hydrogen;unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; unsubstituted C₁-C₃alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; and C₁-C₂alkylamino or C₁-C₂ dialkylamino and halo; R₅ is hydrogen; and R₇ isselected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl;unsubstituted C₁-C₃ alkylthio or alkoxy; and C₁-C₂ alkylamino or C₁-C₂dialkylamino; and halo.
 6. The compound according to claim 1, wherein R₅is guanidinylamino and R₁₁ is hydrogen.
 7. The compound according toclaim 1, wherein R₄ is guanidinylamino and R₁₁ is hydrogen.
 8. Thecompound according to claim 7, wherein: R₅, R₆ and R₇ are eachindependently selected from hydrogen; methyl; ethyl; methoxy;methylthio; hydroxy; thio; cyano; amino and halo; and R₂ is hydrogen. 9.The compound according to claim 1, wherein the compound is:[(8-Methylquinolin-7-yl)amino]guanidine; or [(4-Methylbenzimidazol-5-yl)amino]guanidine.
 10. A pharmaceutical composition comprising: (a) asafe and effective amount of a compound of claim 1; and (b) apharmaceutically-acceptable carrier.
 11. A method for preventing ortreating a disorder modulated by alpha-2 adrenoceptors, by administeringto a mammal in need of such treatment, a safe and effective amount of analpha-2 adrenoceptor agonist compound according to claim
 1. 12. A methodfor preventing or treating a disorder modulated by alpha-2adrenoceptors, wherein the disorder is chosen from the groupscomprising, nasal congestion, otitis media, sinusitis, asthma, pain,migraine, substance abuse and addiction, gastrointestinal disorder,ulcer, stomach hyperacidity, benign prostatic hypertrophy, byadministering to a mammal in need of such treatment, a safe andeffective amount of an alpha-2 adrenoceptor agonist compound accordingto claim
 1. 13. A method of treating or preventing nasal congestion byadministering to a mammal in need of such treatment a safe and effectiveamount of a compound according to claim
 1. 14. A method of treating orpreventing nasal congestion by administering to a mammal in need of suchtreatment a safe and effective amount of a compound according to claim9.
 15. The method of claim 12, wherein the disorder is otitis media. 16.The method of claim 12, wherein the disorder is sinusitis.
 17. A methodfor preventing or treating a respiratory disorder, wherein the disorderis chosen from the group comprising cough, chronic obstructive pulmonarydisease and asthma, by administering to a mammal in need of suchtreatment, a safe and effective amount of a compound according to claim1.
 18. A method for preventing or treating a respiratory disorderaccording to claim 17, wherein the disorder is asthma.
 19. A method forpreventing or treating an ocular disorder modulated by alpha-2adrenoceptors, by administering to a mammal in need of such treatment, asafe and effective amount of a compound according to claim
 1. 20. Amethod for preventing or treating an ocular disorder according to claim19 wherein the disorder is chosen from the group comprising ocularhypertension, glaucoma, hyperemia, conjunctivitis, and uveitis andglaucoma.
 21. A method for preventing or treating an ocular hypertensivedisorder according to claim 20 wherein the disorder is glaucoma.
 22. Amethod for preventing or treating a gastrointestinal disorder modulatedby alpha-2 adrenoceptors by administering to a mammal in need of suchtreatment, a safe and effective amount of an alpha-2 adrenoceptoragonist compound according to claim
 1. 23. A method for preventing ortreating a gastrointestinal disorder, according to claim 22, wherein thedisorder is chosen from the group comprising diarrhea and irritablebowel syndrome.
 24. A method for preventing or treating agastrointestinal disorder, according to claim 22, wherein the disorderis diarrhea.
 25. A method for preventing or treating migraine byadministering to a mammal in need of such treatment, a safe andeffective amount of a compound according to claim
 1. 26. A method forpreventing or treating pain by administering to a mammal in need of suchtreatment, a safe and effective amount of a compound according to claim1.
 27. A method for treating substance abuse by administering to amammal in need of such treatment, a safe and effective amount of acompound according to claim 1.